CA1113469A

CA1113469A - Process for the preparation of thienopyridine derivatives

Info

Publication number: CA1113469A
Application number: CA307,086A
Authority: CA
Inventors: Andre Bousquet; Emile Braye
Original assignee: Parcor SARL
Current assignee: Parcor SARL
Priority date: 1977-07-12
Filing date: 1978-07-10
Publication date: 1981-12-01
Also published as: IT7850225A0; GB1599728A; FI67852B; PH14288A; DD136838A5; ATA468978A; FI782044A7; LU79823A1; RO74931A; FR2397417A1; NO782411L; JPS5419994A; PL115368B1; DK155285C; YU148278A; ES471403A1; SU900813A3; JPS6339598B2; AR224501A1; FR2397417B1

Abstract

PROCESS FOR THE PREPARATION OF THIENOPYRIDINE DERIVATIVES.
ABSTRACT OF THE DISCLOSURE
This invention relates to a process for the preparation of compounds having the general formula :

(I) in which : R1 represents a hydrogen atom, an optionally substitu-ted alkyl, aryl or aralkyl radical; R2 and R3 are the same or different and represent independently a hydrogen atom, a lower alkyl, aryl or heterocyclic radical; and R4 represents a hydrogen atom or an alkyl, cycloalkyl, alkoxy carbonyl, carboxy, aryl or heterocyclic radical, comprising reacting a compound having the formula:
(II) in which R1, R2 and R3 are as defined above, with a compound having the formula :
(III) in which R4 is as defined above; X is a halogen atom, or an optionally substituted alkoxy, thioalkyl or amino group; and Y
represents an optionally substituted alkoxy, thioalkyl or amino group, or a group of the formula :

Description

1~3~i3 This invention relates to a process for the preparation of thienopyridine derivatives.

In French patent 75 03 968 and its first certi-ficate of addition 75 23 786 is described a process for the preparation of thienopyridine by reaction of an optionally substituted 2-~-thienyl-ethylamine with formaldehyde in the presence of an acid. Said reaction is preferably effected in two steps, first by reacting ~-thienylethylamine with formaldehyde, and then by cyclization of the resulting material in anhydrous medium, with an anhydrous acid. However, the rate of conversion of the starting material is only of the order of 60-65%, which necessitates a recycling of the unreacted starting material.
lS In addition, said process does not permit the prepa-ration of thienopyridine substituted at 4-position by means of the Pictet Spengler reaction, by action of an aldehyde on a thienylethylamine derivative.
It is also known to prepare 1,2,3,4-tetrahydroisoqui-nolines from N-benzoyl derivatives of beta-arylamine and chloromethyl-methylether, as disclosed in Chemical Communications, 1969, 1283-4. It should be noted, however, that cyclization occurs on a highly activated benzene nucleus and that the reaction site is an amide.
The purpose of the present invention is to overcome said drawbacks by providing a process which makes it possible both to obtain derivatives substituted at 4-position and to obtain markedly higher yields and conversion rates.
Thus, this invention relates to a process for the preparation of compounds having the general formula :

~,R2 R

in which : Rl represents a hydrogen atom, an optionally substituted alkyl, aryl or aralkyl radical; R2 and R3 are the same or different and represent independently a hydrogen atom, a lower alkyl, aryl or heterocyclic radical; and R4 represents a hydrogen atom or an alkyl, cycloalkyl, alkoxy carbonyl, carboxy, aryl or heterocyclic radical, comprising reacting a compound having the formula :
R3 R2 (II) in which Rl, R2 and R3 are as defined above, with a compound having the formula :

X - CH - Y (III) in which R4 is as deined above; X is a halogen atom, or an optionally substituted alkoxy, thioalkyl or amino group; and Y
represents an optionally substituted alkoxy, thioalkyl or amino group, or a group of the formula :
- O - C - R

in which R is a lower alkyl or aryl radical; or both the groups X and Y, together with the carbon atom to which they are attached, form a 6-membered hexahydro-S-triazinic, trioxannic or trithianic heterocyclic nucleus, in an inert solvent, at a temperature between o and 150C and in an anhydrous medium, and, if desired, liberating the free base.
Those compounds of formula I where R4 is other than hydrogen are novel compounds.

: - 3 The compounds of the formula (III) which are used in the process according to this invention may be illustrated by the following compounds, depending on the nature of X and Y :
a) a halogenomethyl ether of the type XCH - O - R5 or X - CH - 0 - CH - X
in which X is a halogen atom such as Cl or Br and R5 is a lower alkyl or aryl radical;
b) a halogenomethyl thio ether of the type 1.0 X - ~H - S - R6 or X - CH - S - CH - X
in which X is a halogen atom such as ~1 or Br and R6 is a lower alkyl or aryl radical;
c) a halogenomethyl ester of the type XCH O C R
in which X is a halogen atom such as Cl or Br and R7 is a lower alkyl or aryl radical;
d) a S-hexahydro-S-triazine having the formula :

I N ~ , ~ 4 ~4-1 IH

R / ~ ~ ~ N \ R

or an amino Rderlvative haviny the ro ~ la :

N - ~H - N
lQ 4 R12 in which formulae R8, Rg, Rlo/ Rll and R12 are lower alkyl radicals which may, between them, form a nitrogen bridge, or the same or different aryl radicals;

. ,~ . , _ -e) a trioxan having the formula :

R--~ ~CH~R4 0~0 or a polyoxymethylene derivative having the formula R13 ~ 0-CH2 tn OR14 in which R13 and R14 are hydrogen atoms or the same or different lower alkyl or aryl radicals, and n ~ 1 f) a trithian having the formula :

~S~
R4 - lCH C~ R4 ~CIH~

or a polythiomethylene derivative having the formula :
R15 - (ScH2)n SR16 in which R15 and R16, which may be the same or different, are lower alkyl or aryl radicals and n ~ 1.
The reaction between the compound of the formula (II) and the compound of the formula (III) is conducted within an inert solvent at a temperature of 0-150C, but preferably between room temperature and the boiling point of the more volatile compound which is generally one of the solvents used.
This reaction occurs presumably via the formation of an intermediate compound which is not isolated, but cyclized ln situ, as discussed hereinafter.
However, the cyclization of this intermediate compound requires the presence of an acid which is either generated in the medium by the reaction for the formation of the intermediate, or added when it is L~ ~

not provided by said reaction for the formation of the interme-diate. The in situ formation of acid is dependent on the nature of the compound of the formula (III); Thus, for the compounds of the formula (III~ of types a, b and c one notes the formation of such an acid of the formula XH which functions as cyclization agent, whereas no acid is formed in the case of the compounds of the formula (III) of types d, _ and f.
In the latter case, use is made of a reactio~solvent which contains an acid which may be, for example : an inorganic acid, which is preferably anhydrous, such as hydrochloric, sulfuric, hydrobromic and phosphoric acids; an orsanic carboxylic acid such as oxalic, acetic, monochloracetic acids, or a sulfonic acid such as methanesulfonic and benzenesulfonic acids.
In the case where the acid is generated in the medium, it is preferred to add the compound of the formula (III) to the so-lution of the compound of the formula (II), although the reverse procedure is also possible. In the other cases, it is preferred to add a mixture of compounds of the formulae (II) and (III) to the reaction solvent containing the cyclization acid.
Most of the times, the reaction occurs rapidly; but it may sometimes be advantageous to apply external heating at the end of the reaction, to speed up same.
The reaction may be effected at atmospheric pressure or at superatmospheric pressure; but atmospheric pressure is generally sufficient.
The reaction is conducted within a solvent inert withrespect to the reagents, particularly with respect to the ccmpounds of the formula (III). Said solvent should be anhydrous, because water decomposes the compounds of the formula (III). It ls preferred to use an aprotic solvent, which may be of polar nature, such as , ~, dimethylformamide, dimethylsulfoxide, hexamethyl phosphoro-triamide or another solvent, such as benzene, toluene;a chlori-nated solvent such as a chlorinated hydrocarbon; or light ethers.
It is advantageous to conduct the reaction within a solvent in which the halide of the compound of the formula (I) is scarcely - if at all - soluble because, indeed, it is then possible to isolate the salt of the compound of the formula (I),at the end of the reaction, by filtration of the resulting precipitate. In addition, this procedure provides excellent yields, in addition to convenient processing.
The compounds of the formulae (II) and (III) are reacted in stoichiometric amounts or, if desired, with an excess of compound of the formula (III) up to about 50~.
While not wishing to be bound by any reaction mechanism, Applicant thinks it should be said that the reaction occurs in two steps, which two steps are not distinct, practically :

~ _ _ CH-CH-NH-R

R4 S CH-C~-N-Rl HX
+ X - CH - Y ~ R4 +

acld ~ ~ C~ ~-R

Thus, the cyclization occurs with formation of an alcohol, a mercaptan, an amine or water.
Said cyclization is obtained with very good yields and con-version rates of the starting material. Thus, in the cyclizations where the reagent is chloromethyl methyl ether, or chloromethyl methylthioether, the conversion rate of the compound of the formu-la (II) is close to 100~ and the yields are of the order of 90-95~.
Also, by means of the process of this invention, it is possi-ble to obtain thienopyridine derivatives in which the group R4 isan aryl group such as the phenyl group, a heterocyclic group such as the 2-thienyl group, an aliphatic or cycloaliphatic radical or a functional group such as alkoxy-carbonyl, carboxy.
The preparation of the starting reagents of the formula (III) lS is readily effected by procedures known in the literature and which are outside the scope of this invention. Some compounds of the formula (III~ are unstable and, ther~fore, they should be prepared just prior to use in the process of this invention in which they are used without further purification.
The following non-limiting Examples are given to illustrate the process of this invention.
Example 1 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c/ yridine hydrochloride To a solution of 50.8 g (0.2 M) ~-(2-chloro-benzyl)-2-(2-thienyl)-ethylamine in 70 ml dimethylformamide heated at 60~C
is added, over 7 minutes, 22.7 g (0.24 M) chloromethylmethylether.
The temperature of the reaction medium is maintained at 60C
throughout the addi~n step by cooling with water. Thirty minutes after o~letion of the chloromethylmethylether addition, the medium is ,~, cooled to 20C. The desired product, which has precipitated out, is filtered and washed with 2 x 70 ml acetone, to give 45.1 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (Yield : 75~).
Treatment of the filtrates produces another 9 g of the desired product (Yield: 90~O. M.p. = 190C).
Example 2 Preparation of 5- (2-chloro-benzyl)-4-ethoxycarbonyl-4~5~6~7 tetrahydro-thieno/3,2-c7pyridine hydrochloride Into a three-necked 250 ml flask are added 25.1 g (0.lM) N- (2-chloro-benzyl)-2- (2-thienyl)ethylamine dissolved in 30 ml dimethylformamide. Ethyl 2-chloro-2-ethoxy-acetate (18.3 g;
0.11 M) is then added over 6 minutes, and the resulting material is heated at 80C for 4 hours after which the desired product begins to lS precipitate out. After cooling of the medium, the product is fil-tered off and recrystallized from 3 x 20 ml acetone, to give 20.5 g 5- (2-chloro-benzyl)-4-ethoxy-carbonyl-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (Yield : 55%).
Treatment of the filtrates provides another 10 g crude pro-duct (M.P. = 156C). The crude product is obtained analytically pure by recrystallization from ethanol-isopropyl ether (Overall yield: 81.8%).
Example 3 Preparation of 5-(2-chloro-benzyl)-4- (2-thienyl)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride a) Preparation of (2-thienyl)chloromethylmethylether.
Into a stirred flask are added 112 g (1~) (2-thienyl)carbo-xaldehyde, 50 g (1.55 M) methanol, 125 ml methylene chloride and 150 g sodium sulfate. The reaction medium is cooled to -35C and a stream of dry gaseous hydrochloric acid is bubbled through to saturation-~hlle preventing the ter~erature from exceeding 20C.After interr~tior g 4Ç~3 of the bubblin~ of hydnx~oric acid, the reaction medium is left at -20C, with stirring, for 2 hours. The methylene chloride is then evaporated off at -20C to give the crude 12-thienyl)-chloromethyl-methylether.
S b) Preparation of 5-(2-chloro-benzyl)-4-(2-thienyl)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride.
N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine is reacted with the ether prepared in (a) above, in a manner analogous to that described in Example 1,to give the desired compound (melting point of the base : 109C).
Examples 4 and 5 The following compounds are prepared in a manner analogous to that described in Example 1 :
5-(2-chloro-benzyl)-4-phenyl-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (M.p. of the base : 95C).
5-(2-chloro-benzyl)-4-isopropyl-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (M.P. of the base: 172C).
respectively, from N-(2-chloro-benzyl)-2-(2-thienyl)ethyl-amine and the following compounds :
~ -chlorobenzyl-methylether, l-chloro-l-ethoxy-2-methyl-propane.
Example 6 Preparation of 4,5,6,7-tetrahYdro-thieno~3,2-c7pyridine hydrochloride .

To a solution of 12.7 g (0.1 M) 2-(2-thienyl)ethylamine in 20 ml dimethylformamide heated at 55C are added, over 10 minutes, 8.05 g (0.1 M) chloromethylmethylether diluted in lOml dimethyl-formamide. After addition of the chloromethylmethylether, the mediumis maintained at 70C for 2 hours,and is then cooled to room temperature. The desired product precipitates out and is rinsed 3~

with acetone, to give 5.5 g 4,5,6,7-tetrahydro-thieno~3,2-c7-pyridine hydrochloride (M.p. = 225C; Yield : 31%).
Example 7 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno/3,2-c7pyridine hydrochloride a) Preparation of chloromethylmethylthioether Into a 1 litre capacity three-necked flask are added 274 g (2.3 M) thionyl chloride and 400 ml methylene chloride. The mixture is refluxed (41C) and 156 g dimethylsulfixide is slowly added thereto. A substantial gas evolvement is noted throughout the addition:it consists of SO2and HCl. Slight heating must be maintained to keep the medium under refluxing conditions. On o~letion of the dimethylsulfoxide addition, a nitrogen stream is bubbled through to remove the dissolved hydrochloric acid. The reaction medium (333 g) is used as such in the cyclization step described below. Gas phase chromatographic quantitative determination gives the following results :
- chloromethylmethylthioether : 56.77%
- methylene chloride : 33 %
b) 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride To 52 g (0.2 M) N-(2-chloro-benzyl)-2-(2-thienyl)ethylamine dissolved in 60 ml dimethylsulfoxide and heated at 60C are added, over 30 minutes, 51 g (0.3 M) crude chloromethylmethylthioether prepared in step (a) above. The temperature of the reaction medium increases gradually and it is maintained at 80-85C throughout the addition step, by o~oling with water. When addition of chloromethyl methylthioether is completed,the medium is cooled to 6C. The desired product precipitates out rèadily.After filtration and washing with 2 x 70 ml acetone, there are obtained 44.1 g 5-(2-~ ~ ~ 3L~ ~

chloro-benzyl)-4~5r6~7-tetrahydro-thieno~3~2-c/pyridine hydro-chloride (Yield : 73.5%). Treatment of the filtrates provides another 10 g of the desired product (Yield : 90% M.p. = 190C).
The resulting crude product contains 1-2~ impurities and may be S made analytically pure by recrystallization from ethanol.
Example 8 Preparation of -5-(2-chloro-benzyl~)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride The same compound as in Example 1 is prepared in the following manner :
66.5 g (0.44 M) chloromethyl pivalate is reacted by heatir.g, for 3 hours, with a solution of 103 g (0.4 M) N-(2-chloro-benzyl)-2-(2--thienyl)ethylamine in 300 ml dimethylsulfoxide, to give the title compound in a yield of 51~.
Example 9 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c7 yridine hydrochloride To 42 ml dimethylformamide in which are dlssolved 0.25 m~le gaseous hydrochloric acid and heated at 40~C is added, over 2 minutes, a mixture of 25.15 g (0.1 M) ~-(2-chloro-benzyl)-2-(2-thienyllethylamine and 15.3g (0.033 M) s.hexahydrotriazine of o.chlorobenzylamine. The reaction is exotherm~1 and, during the addition, the reaction must be cooled with water to maintain the temperature of the reaction medium below 70C. After completion of the addition, stirring is continued for a further 30 minutes and the material is then cooled. The desired product is filtered off and washed twice with acetone, to give 17.3 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno/3,2-c/pyridine hydrochloride.

Treatment of the filtrates provides another 10 g of the desired product (Overall yield : 90~).

.~

Examples 10-12 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c/pyridine hydrochloride Using the same procedure as described in Example 9,the title compound is obtained by substituting s.hexahydrotriazine of o.chlorobenzylamine with :
- s.hexahydrotriazine of n.butylamine (Yield ~ 90~) - urotropine (yield : 60~) - paraformaldehyde (yield : 83%).
Example 13 Preparation of 4,5,6,7-tetrahydro-thieno~3,2-c7pyridine -hydrochloride To 73 ml dimethylformamide heated at 45C in which are dissolved 0.45 mole gaseous hydrochloric acid, is added, over 25 minutes, a mixture of 17 g (0.2 M)s.hexahydrotriazine of n.
n.butylamine and 26 g 2-(2-thienyl)ethylamine. The temperature of the medium is maintained at 45C throughout the addition by means of a cold water bath. The desired product precipitates out at the end of the addition. Filtration gives 22.16 g 4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (Yield : 65%).
Example 14 Preparation of 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno/3,2-c7pyridine hydrochloride To 2.25 G (0.075 M) paraformaldehyde suspended in 20 ml dimethylformamide are added 9.61 g (0.1 M) methanesulfonic acid.
The medium being at a temperature of 72C, 13 g (0.05 M) N-(2-chloro-~enzyl)-2-(2-thienyl)ethylamine dissolved in 5 ml dimethylformamide are added over 2 minutes. The temperature of the reaction medium reaches 90C. The reaction medium is then cooled to 2QC and poured over 50 ml 4N sodium hydroxide. The ~ L~ ~

material is extracted with l x 30 ml and then 1 x 20 ml methylene chloride. The organic phases are ~ined, dried over sodium sulfate and evaporated, to give an oil which is taken up into 30 ml ethanol in which are dissolved 0.15 mole gaseous hydrochloric acid. After par~ial evaporation of the ethanol, the desired product precipitates out. It is filtered, washed with acetone and dried, to give ll.35 g 5-(2-chloro-benzyl)-4,5,6,7-tetrahydro-thieno~3,2-c7pyridine hydrochloride (Yield : 75.6~).

-6' SUPPLEMENTARY DISCLOSURE

The purpose of the present supplementary disclosureis to illustrate the preparation of a further group of compounds falling within the scope of the original dis-closure. More specifically, the compounds which can be pre-pared in accordance with the process of the present invention correspond to the following general formula IV:

~R2 N~R

in which:
Rl represents (a) hydrogen;
(b) a Cl-C8 alkyl;

(c) ( )m ( )n ~ wherein m is 1 or 2;
R5 is hydrogen or a C1 to C4 alkyl;
n is O or l;
R is hydrogen, a Cl to C4 alkyl, a Cl to C4 alkoxy, halogen, a C1 to C4 acyl, nitro, phenyl or the chain -CH=CH-CH=CH- attached to the phenyl ring thereby to form a fused benzene ring or the group r~3;
x is 1, 2 or 3;

(d) -CH2-CH=CH ~ wherein R and x are as defined previously; or (e) -CH ~ l, and R2 and R3 are each hydrogen or an alkyl containing 1 to 8 carbon atoms; and R4 is hydrogen, Cl-C6 alkyl, Cl-C6 alkoxy carbonyl, phenyl and thienyl.
The process for preparing the compounds of the formula IV is the same as used for preparing compounds of formula I disclosed in the original disclosure where R4 stands for hydrogen. Compounds which were prepared in accordance with the process outlined in the original disclosure are illustrated and characterized in the following Table I:

1~

~ n C~,~h Rl Compotlnd~o. ~ p. or b.p. l(:) CH3 b.p. 52-54/0,1 mQ llg (C 12)6CH3 b.p. 118/0.5 mm llg 3 _CH2~) 2~0 Ibydrocbloridc) 4 --C112~ 208-210 (hydrochloridc) C~3 -cll2~cJl3 215 (hydrochloride) 6 -C~12~c~3 260 (hydrochloridc) 7 -CH2~ 168 (~oales~e) 8 -C112~ 216 ~metbiodide) 9 _C~12~3p 215 ~hydrochloride) r~

- 2~ 190 (hydrochloride) 11 -C112~3 . 212 (maleatc) - Cl 12 -cn2~ . 182 (~etbiodide) Cl T, n1E I (continuod) COD~Onnd ~'- Rl M.p. or ~).~ (C~
13 _C~2~ 200 (hydrocbloride) Cl 14 --C~2~01 240 (hydrochloride) Cl 2~ 200 (hydrocblorlde) 16 --C112~:l 210 (hydrocHloride) Cl ~7 _cr2~ 122 OR
18 _CHz~ OR . 240 (hydrochloride) 19 -CH2~C-COCH3 86 -C1~2~ gO
0~
21 --CH2~ . 200 (hydrochloride) 22 ~2~ocJ~3 215 (hydrochloride) 23 --Cl32~oc~l3 100 (methiodid~) 24 -CH2~ocll3 210 (hydsochloride) ocn3 --CR2~ 19~D (hydrochloride) ~JCL13 ~AnLE I (contin~lcù) Comno~lnd ?~'o. 1 ~I.p. or h.~, (C) 26 -Cl~2~ocll3 1~-19~(hydrochloride) OC1~3 27 -C~2~ 3 205 ~hydrocllloriae) C~3 OC~3 28 -C~2~ocH3 195 (~ethiodide) C1~3 29 --C112~oc~3 230--235 (bydrochloride) OC~3 -CH2~ . 180 (hydrochloridc) No2 31 --Cn2~3~o2 119-121 32 --CH2--CU243 226 ~hydrochlorideJ

33 -C~2-CI3-Cll~ ?76 (2~ydrochloride) 34 --CH2~ 120 ... , ` ' ~ .
-CH2~3-C1 200 (h~,Qrochloride) 36 --CHz-CH~OH)~ 164-166 (bydrochloridc) 37 --CU(CH3)-Cll(OH)~ 230 (hydrochloride) TA~LE ~ (continued) - Com~ou~!d ~- Rl M.P. or b.p.(C) -C~2-CII(OJi) ~ 2!0 (hydrochloride) 39 -C~2-C~(OH) ~ F . 124 -C112CII(OH~ ~ Cl 195 (hydrochloride) 41 _cn2cn(ll) ~ ~ 2t6-218(hydrochloride) 42 -CEi2CIi(OEi) ~ 224 (hydrochloride) ~3CO

43 -CL2-C~(OH) ~ C ~170 (h~drochloride) 44 -CFi2-C}l(On) ~ OC~ 206-208(hydrochloride) ~OCli3 i5 -CH2-CH(OH) ~ 106 CO~ .

46 _C~2-CHi(O~ ~15D (ru~ar~te~

- 20 ~

L~

TAB~E ~I

R ~ -R~ .
Co~.pou~d ~'o. 1 M.~. or h.~,(C~

47 -cn2 ~ 79D-194(hydrochloride) p .

48 -C ~ ~ 179-180(hydrochloride) Cl 49 -Ch2 ~ 178-180(bydrochloride) h'2

Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. Process for the preparation of compounds having the general formula:

(I) in which: R1 represents a radical selected from the group consisting of hydrogen, benzyl and benzyl substituted by a halogen; R2 and R3 are hydrogen; and R4 represents a radical selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl and thienyl, comprising reacting a compound having the formula:

(II) in which R1, R2 and R3 are as defined above, with a compound having the formula:

(III) in which R4 is as defined above; X is halogen; and Y repre-sents a radical selected from the group consisting of a C1-C3 alkoxy, a C1-C3 thioalkyl, and a group of the formula:

in which R is a radical selected from a C1-C5 lower alkyl, or both the groups X and Y, together with the carbon atom to which they are attached, form a 6-membered nucleus selected from hexahydro-S-triazinic, trioxannic and a urotropine nucleus, in an inert solvent, at a temperature between 0 and 150°C and in an anhydrous medium and, if desired, liberating the free base.

2. Process as claimed in Claim 1, wherein the reaction is effected between room temperature and the boiling point of the more volatile compound.

3. Process as claimed in Claim 1, wherein said inert solvent is a polar aprotic solvent such as dimethyl-formamide, dimethylsulfoxide, hexamethylphosphorotriamide, or benzene or a chlorinated solvent such as a chlorinated hydro-carbon or a light ether.

4. Process as claimed in Claim 3, wherein the solvent contains an inorganic or organic acid of carboxylic or sulfonic type.

5. Process as claimed in Claim 4, wherein said acid is hydrochloric acid or methane sulfonic acid.

6. Process as claimed in Claim 3, wherein the solvent is selected so as to be a non-solvent for the halide of the compound of the formula (I).

7. Process as claimed in Claim 1, wherein the compound of the formula (III) is reacted in an amount com-prised between the stoichiometric amount and a molar excess of 50% with respect to the compound of the formula (II).

8. Process for the preparation of compounds having the general formula:

wherein R1 is hydrogen, benzyl or benzyl substituted by a halogen atom, R2 and R3 are both hydrogen and R4 is C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl or thienyl, which com-prises reacting a compound having the formula:

wherein R1, R2 and R3 are as defined above, with a compound of the formula:

in which R4 is as defined above; X is halogen; and Y is a C1-C3 alkoxy, a C1-C3 thioalkyl, and a group of the formula:

wherein R is a C1-C5 lower alkyl, or both the groups X and Y
together with the carbon atom to which they are attached, form a 6-membered nucleus selected from hexahydro-S-triazinic, tri-oxannic or a urotropine nucleus, in an inert solvent at a temperature between 0 and 150°C and in an anhydrous base, and, if desired, liberating the free base.

9. Compound having the general formula:

wherein R1 is hydrogen, benzyl or benzyl substituted by a halogen atom, R2 and R3 are both hydrogen, and R4 is C1-C6 alkyl, C1-C6 alkoxy, phenyl and thienyl, when prepared by the process defined in Claim 8 or by an obvious chemical equiva-lent.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE

Process for the preparation of thieno-pyridine derivatives having the formula:

(I) in which:
R1 represents (a) hydrogen;
(b) a C1 to C8 alkyl;

(C) wherein m is 1 or 2;
R5 is hydrogen or a C1 to C4 alkyl;
n is 0 or 1;
R is hydrogen, a C1 to C4 alkyl, a C1 to C4 alkoxy, halogen, a C1 to C4 acyl, nitro, phenyl, or the chain -CH=CH-CH=CH- attached to the phenyl ring thereby to form a fused benzene ring or the group x is 1, 2 or 3;

(d) where R and x are as defined previously; or (e) , and R2 and R3 are each selected from the group consisting of hydrogen and alkyl containing 1 to 8 carbon atoms, and R4 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy carbonyl, phenyl or thienyl, which comprises reacting a compound having the formula:

(II) in which R1, R2 and R3 are as defined above with a compound having the formula:

(III) in which R4 is as defined above; X is halogen and Y is a C1-C3 alkoxy, a C1-C3 thioalkyl, or a group of the formula:

in which R is a C1-C5 lower alkyl, or both X and Y, together with the carbon atom to which they are attached, form a 6-membered nucleus selected from hexahydro-S-triazinic, trioxannic or a urotropine nucleus, in an inert solvent, at a temperature of between 0 to 150°C and in an anhydrous medium and, if desired liberating the free base.

SD 11 Process for the preparation of thieno-pyridine derivatives having the formula:

(I) in which:
R1 represents (a) a C1 to C8 alkyl;

(b) wherein m is 1 or 2;
R5 is hydrogen or a C1 to C4 alkyl;
n is 0 or 1;
R is hydrogen, a C1 to C4 alkyl, a C1 to C4 alkoxy, halogen, a C1 to C4 acyl, nitro, phenyl, or the chain -CH=CH-CH=CH- attached to the phenyl ring thereby to form a fused benzene ring or the group ;
x is 1, 2 or 3;

(C) where R and x are as defined previously; or (d) , and R2 and R3 are each selected from the group consisting of hydrogen and alkyl containing 1 to 8 carbon atoms, and R4 is hydrogen, which comprises reacting a compound having the formula:

(II) in which R1, R2 and R3 are as defined above with a compound having the formula:
X - CH2 - Y (IIIA) in which X is halogen and Y is a C1-C3 alkoxy, a C1-C3 thio-alkyl, or a group of the formula:

in which R is a C1-C5 lower alkyl, or both X and Y, together with the carbon atom to which they are attached, form a 6-membered nucleus selected from hexahydro-S-triazinic, trioxannic or a urotropine nucleus, in an inert solvent, at a temperature of between 0 to 150°C and in an anhydrous medium and, if desired liberating the free base.